During the past year, we have created and tested new vaccine candidates, including envelope proteins and fusion peptides displayed on carrier proteins. In addition, we have continued our work testing different methods and routes of administration as well as prime/boost combinations to further optimize HIV vaccine strategies. Proteins with different adjuvants and nanoparticles were also tested. Several candidate vaccines that elicited promising immunogenicity data in preliminary studies are being tested further. Pre-clinical study in guinea pigs and monkeys showed that a stabilized envelope trimer with Alum as the adjuvant elicited serum neutralizing activities. This envelope trimer vaccine candidate entered into a human clinical trial in March 2019 (VRC 018 trial). Furthermore, broadly HIV-1 neutralizing activity directed to fusion peptide, which is an essential component of HIV fusion machinery, was generated in multiple vaccine-test animal models including mouse, guinea pig and non-human primate. Studies to understand development of broadly neutralizing antibodies using different human immunoglobulin knock-in mice are ongoing. These studies are testing novel immunogens designed to generate neutralizing antibodies to HIV-1 vulnerable sites: the CD4 binding site, V2 apex and membrane-proximal external region (MPER). For antibody development, we have applied targeted mutations to several broadly neutralizing anti-HIV-1 antibodies (bNAbs) that have been isolated from HIV+ donors. The mutations are designed to increase breadth, potency and half-life to improve potential efficacy for therapeutic application and to decrease immunogenicity to allow for more effective and longer lasting in vivo function. There are also structure-based mutations designed to improve affinity and neutralization potency. Additionally, mutations to improve biophysical properties and manufacturability have been designed in collaboration with Just Biotherapeutics, with plans for further development and use in clinical trials. We are also working with collaborators to develop tri-specific anti-HIV-1 antibodies that combine three different anti-HIV-1 specificities in one IgG-like molecule for both HIV-1 prevention and therapy, one of which has advanced to phase I clinical trials. In another collaborative effort, we are developing improved N6-like antibodies for use in HIV-1 therapy. The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. We have developed immunomodulatory proteins referred to as T cell engagers (TCEs) that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. These TCEs could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. In addition, we have started collaborative work to develop TCEs that activate T cells to lyse HIV-1 infected cells.